A steady accumulation of data argues that prion-like mechanisms feature in the pathogenesis of most or all age-dependent neurodegenerative diseases. For both the mammalian and fungal prions, we have succeeded in producing a variety of synthetic strains. The physical characteristics of the synthetic prion strains breed true upon passage and are predictive of infectivity: there is a clear relationship between the length of the incubation time and the structural stability for the mammalian prion strains. The ability to create different infectious conformations and introduce them into yeast makes the [PSI+] system uniquely well suited for studying how changes in the conformation of proteins determine their physiological impact. While elucidating the molecular mechanisms that specify the properties of prion strains is likely to create improved models for experimental AD, it will probably be insufficient in the quest for effective therapeutics. That being the case, we plan to study cultured neurons produced from fibroblasts using stem cell technology. A systematic screen of TFs identified a pool of 3 TFs that can induce mouse fibroblasts to differentiate into neurons. We plan to produce neurons from human fibroblasts obtained from carriers with APP or PrP gene mutations that cause familial AD or CJD, respectively. These neurons will be used in studies on the propagation of PrP and A? amyloids in cells and transgenic mice. Deciphering the language of prion strains will open many new avenues of investigation that are likely to reach far beyond the pathogenesis of neurodegeneration. We do not understand the rules of protein-based inheritance and have little appreciation of how prions function in the normal physiology of the cell as well as cause neurodegeneration. PUBLIC HEALTH RELEVANCE: More than 5 million Americans suffer from Alzheimer's disease (AD) caused by brain degeneration. Of all the neurodegenerative disorders, the prion diseases are arguably the best understood. We propose studies directed toward elucidating the pathogenic mechanisms responsible for neurodegeneration in AD and Creutzfeldt-Jakob disease. Able to create distinct prion strains from recombinant proteins produced in bacteria that infect mice or yeast, we plan to elucidate the structures of these synthetic prion strains and study their propagation in mouse and human neurons produced from fibroblasts by a remarkable new stem cell technology. Dissecting the processes that feature in the pathogenesis of prion-induced neurodegeneration may provide novel insights that direct development of effective therapeutics not only for the prion diseases but also for the most common neurodegenerative disorder, AD. REVIEW OF INDIVUDUAL COMPONENTS OF THE PROGRAM PROJECT CORE A: ADMINISTRATIVE CORE;Dr. Stanley Prusiner, Core Leader (CL) DESCRIPTION (provided by applicant): The Administrative Core performs all administrative, accounting and clerical work related to the Program, including production of manuscripts and program reports, preparing financial reports, reviewing expenditures, monitoring budgets and coordinating appropriations. An External Advisory Board will be appointed for a term of 5 years to review, annually, the program's progress. As well, an Executive Committee will be appointed to meet quarterly. A strong Administrative Core is vital to the success of this Program. PUBLIC HEALTH RELEVANCE: Not provided.